Efficiently Computing NMR ¹H and ¹³C Chemical Shifts of Saccharides in Aqueous Environment

Determining the structure of saccharides in their native environment is crucial to understanding their function and more accurately targeting their utilization. Nuclear magnetic resonance observables such as the nuclear Overhauser effect or spin-spin coupling constants are routinely utilized to study saccharides in their native water environment. However, while highly sensitive to the local environment, chemical shifts are mostly overlooked, despite being commonly measured for compounds identification. Although chemical shifts carry considerable structural information, their direct association with structure is notoriously difficult. This is mostly due to the similarity in the chemical nature of most saccharides causing similar physicochemical environments close to sugar C and H atoms, resulting in comparable chemical shifts. The rise of computational power allows one to compute reliable chemical shifts and use them to determine atomistic details of these sugars in solution. However, any prediction is severely limited by the computational protocol used and its accuracy. In this work, we studied a set of 31 saccharides on which we evaluated various computational protocols to calculate the total number of 375 ¹H and 327 ¹³C chemical shifts of sugars in an aqueous environment. Our study proposes two cost-effective protocols for simulating ¹H and ¹³C chemical shifts that we recommend for further use. These protocols can help with the interpretation of experimental spectra, but we also show that they are also capable of structure prediction independently. This is possible because of the low mean absolute deviations of calculated shifts from the experiment (0.06 ppm for ¹H and 1.09 ppm for ¹³C). We explore different solvation methods, basis sets, and optimization schemes to reach such accuracy. A correct sampling of the conformation phase space of flexible sugar molecules is also key to obtaining accurately converged theoretical chemical shifts. The linear regression method was applied to convert the calculated isotropic nuclear magnetic shielding constants to simulated chemical shifts comparable with the experiment. The achieved level of accuracy can help in utilizing chemical shifts for elucidating the 3D atomistic structure of saccharides in aqueous solutions. All linear regression parameters obtained on our extensive set of sugars for all the tested protocols can be reutilized in future works.